Effects of Nicotine on Homeostatic and Hedonic Components of Food Intake

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a stojakovic and others Nicotine and energy 235:1 R13–R31 Review homeostasis

Effects of nicotine on homeostatic and hedonic components of food intake

Andrea Stojakovic1,2, Enma P Espinosa1,3, Osman T Farhad1 and Kabirullah Lutfy1

1Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, Correspondence California, USA should be addressed 2Mitochondrial Neurobiology and Therapeutics Laboratory, Mayo Clinic, Rochester, Minnesota, USA to K Lutfy 3Faculty of Medicine, School of Clinica Biochemistry, Pontifical Catholic University of Ecuador (PUCE), Quito, Ecuador Email [email protected]

Abstract

Chronic tobacco use leads to nicotine addiction that is characterized by exaggerated Key Words urges to use the drug despite the accompanying negative health and socioeconomic ff nicotine burdens. Interestingly, nicotine users are found to be leaner than the general ff food intake population. Review of the existing literature revealed that nicotine affects energy ff obesity homeostasis and food consumption via altering the activity of neurons containing ff orexigenic peptides orexigenic and anorexigenic peptides in the brain. Hypothalamus is one of the critical ff anorexigenic peptides Endocrinology brain areas that regulates energy balance via the action of these neuropeptides. The of equilibrium between these two groups of peptides can be shifted by nicotine leading to decreased food intake and weight loss. The aim of this article is to review the existing

Journal literature on the effect of nicotine on food intake and energy homeostasis and report on the changes that nicotine brings about in the level of these peptides and their receptors that may explain changes in food intake and body weight induced by nicotine. Furthermore, we review the effect of nicotine on the hedonic aspect of food intake. Finally, we discuss the involvement of different subtypes of nicotinic acetylcholine Journal of Endocrinology receptors in the regulatory action of nicotine on food intake and energy homeostasis. (2017) 235, R13–R31

Introduction

Food intake is a complex physiological process necessary integrated with neuronal circuits located in the central for the survival, and is affected by both homeostatic nervous system (CNS) implicated in the control of reward mechanisms as well as palatability of food. The drive and mood to regulate appetite and control energy homeostatic mechanisms involved in the regulation of balance (Sam et al. 2012, Murray et al. 2014). food intake and energy expenditure include endocrine The hypothalamus along with the nucleus of the factors, such as hormones released from the pancreas and solitary tract (NST) in the brain stem, are the major brain gastrointestinal neuroendocrine cells and adipose tissues, regions responsible for the control of energy homeostasis, as well as gut/brain reflexes activated via the autonomic whereas the mesolimbic dopaminergic neurons and other nervous system by peripheral signals from more than 20 brain areas, involved in motivation and emotion, are in regulatory hormones (Wren & Bloom 2007, Kobeissy et al. charge of the hedonic aspects of food intake (Kelley & 2008, Suzuki et al. 2010, Harwood 2012). Neural afferents Berridge 2002, Naleid et al. 2005). Hypothalamic neurons and hormonal signals from the periphery are then largely project to extrahypothalamic regions such as

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10.1530/JOE-17-0166 Review a stojakovic and others Nicotine and energy 235:1 R14 homeostasis

amygdala and the bed nucleus of stria terminalis (BNST), system centered in the hypothalamus and a hedonic establishing connections between metabolism and eating system composed of the cortico-limbic-striatal circuits behaviors (Nestler 2005, Rinaman 2010). (Zoli & Picciotto 2012). Several studies have demonstrated There are two major neuronal areas in the that nicotine reduces body weight by increasing energy hypothalamus identified as regulators of food intake: the expenditure and inhibiting food intake (Hofstetter et al. ventromedial hypothalamus (VMH), recognized as the 1986, Perkins 1992), and that those effects are the result appetite-suppressing center, and the lateral hypothalamus of the modulatory effect of nicotine on both metabolic (LHA), involved in appetite stimulation (Anand & processes and reward circuits (Blendy et al. 2005, Porter 2017). Brobeck 1951). Subsequent studies have found the arcuate Studies performed in rodents have shown that nicotine nucleus of hypothalamus (ARC) as another hypothalamic exert pleasurable effects, similar, although weaker than region with relevant functions in the control of food cocaine and other addictive drugs (Risner & Goldberg 1983). intake, since specific lesions performed in experimental Furthermore, continuous subcutaneous administration of animals at this level were found to promote food intake nicotine in obese rats under high-fat diet reduces food intake (Hamilton et al. 1976). and suppresses further weight gain (Seoane-Collazo et al. The ARC is located in the VMH and is characterized 2014), indicating that these effects of nicotine are the result by the presence of two distinct, but intermingled neuronal of the modulatory effects of nicotine on metabolic processes populations, which have opposite effects on feeding and reward circuits (Blendy et al. 2005, Porter 2017). behavior: the anorexigenic proopiomelanocortin (POMC) Nicotine exerts its effects on energy homeostasis neurons and the orexigenic neuropeptide Y (NPY)/agouti- via nicotinic acetylcholine receptors (nAChRs). These related peptide (AgRP) neurons. The localization of these receptors are widely expressed throughout the central neurons as well as the rich innervations of the area, permit and peripheral nervous systems and particularly well an easy access of the information coming from peripheral positioned in the hypothalamus to alter the expression, organs as well as from multiple parts of the CNS, making secretion or function of neuropeptides that regulate the POMC and NPY/AgRP neuronal groups integrating appetite and food intake, thereby modulating energy

Endocrinology components of peripheral and central inputs to modulate homeostasis and feeding behavior. Nicotine has also been of feeding behavior (Gropp et al. 2005, Aponte et al. 2011). shown to change the levels of certain peptides in the Earlier studies based on stimulation of specific periphery, by acting on nAChRs located in taste, visceral neuronal populations have demonstrated that direct and nociceptive vagal afferent pathways, which also Journal activation of POMC neurons lead to suppression of play a functional role in the ability of nicotine to alter food intake (Zhan et al. 2013). Later, it was shown that food intake (Boucher et al. 2003, Mao et al. 2006, Dani & activation of POMC neurons suppresses appetite by Bertrand 2007, Oliveira-Maia et al. 2009). causing the release of α-melanocyte stimulating hormone Our goal is to describe the effects of nicotine in (α-MSH), the endogenous melanocortin receptor agonist the functional features of the input, output and central (Smart & Low 2003); whereas, AgRP neurons inhibit integration systems that regulate the expression of the POMC neurons possibly by directly blocking melanocortin peptides present in the gastrointestinal tract, adipocytes receptors (Aponte et al. 2011). and hypothalamus to regulate the homeostatic and Tobacco users have been reported to weigh less hedonic aspects of food intake. compared to their same sex- and age-matched non- smokers (Albanes et al. 1987). In contrast, cessation of smoking has been associated with increased food intake, Effects of nicotine on energy homeostasis decrease in metabolic rate and concomitant weight gain (Stamford et al. 1986, Filozof et al. 2004). Indeed, in the Homeostasis in mammals is an intricate process aimed first year after cigarette cessation, ex-smokers have been to maintain a delicate balance between food intake, shown to gain on average about 10 pounds (Audrain- energy expenditure and thermogenic activity. Most of McGovern & Benowitz 2011). Notably, this weight gain the chemical reactions in the cell are pointed at making during abstinence represents an obstacle in smoking the energy in foods available to the various physiologic cessation because it serves as a motivating factor in former systems in the cell. All the energy in foods such as addicts to relapse to tobacco use (Donny et al. 2011). carbohydrates, fats and proteins, can be oxidized in the The regulation of feeding and energy metabolism cells, and during this process, large amounts of energy are involves two interacting brain circuits: a homeostatic released with the ultimate goal of producing adenosine

triphosphate (ATP) for the cells (Suzuki et al. 2010, Myers BAT sympathetic nerve activity and BAT temperature & Olson 2012). through the activation of corticotropic releasing ATP is a labile compound with a structure hormone/factor type 1 (CRH1/CRF1) receptors, indicating characterized by the presence of two last phosphate that one of the mechanisms for nicotine to affect energy radicals with high-energy bonds, consisting of about homeostasis, is by eliciting the thermogenesis of BAT in 12,000 calories under the usual physiologic conditions in the hypothalamus. the human body. Therefore, the removal of each radical In this regard, it is noteworthy to state that in the body liberates about 12,000 calories of energy. If nicotine elicits some of its actions via the endogenous only one of those high-bond phosphates is lost, ATP is opioid enkephalin (Berrendero et al. 2005), which has converted to adenosine diphosphate (ADP). When the been implicated in beiging process, where white fat is second phosphate is liberated, ATP becomes adenosine converted to brown fat (Brestoff et al. 2015). Considering monophosphate (AMP). The energy provided by ATP is that brown fat is metabolically active and leads to greater not heat, but energy for the conduction of nerve impulses, energy utilization and thus body weight loss, it is possible for the active transport of molecules, to cause mechanical that nicotine causes an increase in the expression of movement in the case of muscle or to concentrate solutes enkephalins in fat cells, inducing greater proportion of in the case of glandular secretion among others (De la white to brown fat conversion. Indeed, nicotine has been Fuente et al. 2014). shown to increase thermogenesis in BAT and also increase Energy homeostasis is also dependent on thermogenic its mass via the adrenergic nervous system (Wager- activity. Brown adipose tissue (BAT) is a specialized tissue Srdar et al. 1984, Lupien & Bray 1988, Yoshida et al. critical for non-shivering or adaptive thermogenesis 1990, 1999). However, as stated above, enkephalin may producing heat through mitochondrial uncoupling. be involved in this process. Thus, further studies are BAT, and the newly described brite (‘brown in white’) needed to assess if this action of nicotine is exerted via the adipose tissue (Harms & Seale 2013), are crucial organs endogenous enkephalins, and if this response mediates in facultative thermogenesis (acute response) and have a the ability of nicotine to reduce food intake and alter

Endocrinology great plasticity to respond to long-term changes (e.g. cold energy homeostasis. Additionally, it would be essential of acclimation (Harms & Seale 2013, Vosselman et al. 2013). to explore whether this response is mediated via an BAT mitochondria are distinct from their counterparts action of nicotine on expression of enkephalin locally in in other tissues in that ATP production is not their white adipocytes. Furthermore, given that enkephalin is Journal primary physiologic role. The inner mitochondrial implicated in the rewarding action of nicotine, it is crucial membrane of BAT is loaded with the uncoupling to determine if enkephalin plays any functional role in protein-1 (UCP1). When activated, UCP1 allows protons the regulatory action of nicotine on hedonic aspect of in the intermembrane space to re-enter the mitochondrial food intake. matrix without generating ATP. As a consequence, heat Adipose tissue plays a critical role in the maintenance is generated from the combustion of available substrates of energy homeostasis through the secretion of adipokines, and is distributed to the rest of the body through the which interact with central as well as peripheral organs such circulation (Vosselman et al. 2013, Contreras et al. 2017, as the brain, liver, pancreas and skeletal muscle to control Crichton et al. 2017, Porter 2017). carbohydrate metabolism, lipid metabolism, energy Thermogenesis by UCP1 in BAT is triggered by the expenditure and feeding behavior (Scherer et al. 1995). release of noradrenaline from sympathetic nerve terminals Adiponectin, an adipokine secreted by the white adipose regulated by the hypothalamus (Lowell & Spiegelman 2000, tissue (WAT), and present at high concentrations in the Kelley & Berridge 2002, Cano et al. 2003). Interestingly, it circulation, has been shown to be negatively correlated has been shown that acute or chronic nicotine exposure with body weight, body fat mass, degree of insulin upregulates thermogenesis in BAT. Nicotine increases resistance and weight reduction in obese individuals activity of lipoprotein lipase, improving lipid profile in (Yamauchi et al. 2001, 2007, Kadowaki et al. 2006). Studies rats by decreasing cholesterol and low-density lipoprotein based on central administration of adiponectin in rodents, (Chajek-Shaul et al. 1994) and inhibits fatty acid synthase found that the animals presented significant weight and in cell cultures of adipocytes (An et al. 2007). Moreover, fat mass loss than their vehicle-treated counterparts, and microinjection of nicotine (0.5 mg/kg) into the preoptic that this decrease was a consequence of the increase in area (POA) or the dorsomedial hypothalamus (DMH), but energy expenditure (stimulation of lipid oxidation by not the paraventricular nucleus (PVN) of rats, increases peripheral action on muscle and liver) independent of

food intake, consistent with centrally mediated effects Effects of nicotine on central regulatory mechanisms of (Qi et al. 2004) (Kubota et al. 2007). Likewise, studies energy homeostasis based on receptor-binding assays to evaluate the effect Food intake is a process controlled by the CNS, and it is of nicotine on the function of adipocytes, revealed the stimulated by sensations such as hunger, craving, pleasure presence of nAChRs in adipose tissues, and that both short- and reward (Schwartz et al. 2000). The hypothalamus is or long-term exposure to nicotine stimulates the secretion the main brain region responsible for the control of food of adiponectin into the culture medium, indicating that intake via the actions of certain neuropeptides that are nicotine modulates food intake and body weight at least secreted from two groups of neurons in ARC (Cone 2005). in part by an increase in the secretion of adiponectin One neuronal population secretes orexigenic peptides, through the activation of nAChRs (Liu et al. 2004). such as NPY and AgRP that stimulate appetite, whereas Clinical studies aimed to evaluate the changes of plasma the other set of neurons express anorexigenic peptides, adiponectin levels after smoking cessation, showed that such as α-MSH, a product of POMC, and the cocaine- the mean plasma adiponectin levels of the participants, and amphetamine-regulated transcript (CART), that when compared to the baseline, were significantly suppresses appetite (Meister 2000, Lenard & Berthoud increased after 4 weeks of nicotine withdrawal (Won et al. 2008). Activation of NPY/AgRP-secreting neurons results 2014). Moreover, levels of adiponectin were directly in increased food intake, whereas stimulation of POMC/ related to weight gain after smoking cessation (Inoue et al. CART containing neurons leads to decreased food intake. 2011), suggesting that nicotine regulates body weight by AgRP and α-MSH act on melanocortin-3 and 4 receptors controlling adipose tissue homeostasis. (MC3R and MC4R) to regulate feeding behavior. The AgRP Nicotine has been shown to regulate many processes is an inverse agonist, while α-MSH acts as an agonist of of energy balance by modulating the actions of AMP- melanocortin receptors (MCR). activated protein kinase (AMPK). AMPK integrates The neurons that secrete orexigenic and anorexigenic hormonal and nutritive signals in peripheral organs peptides predominantly project to other neurons located and hypothalamus, thereby playing a major role in in the PVN, lateral hypothalamic area (LHA), perifornical

Endocrinology regulation of energy balance (Kahn et al. 2005). Activated area (PFA), ventromedial (VMN) and dorsomedial nuclei of in state of low energy balance, AMPK stimulates (DMN), establishing an anatomical and functional feeding behavior by modulating mitochondrial fatty connection between these nuclei where the neuropeptides acid oxidation in the hypothalamus, and its activity is Journal that they express can modulate eating behaviors regulated by changes in the expression of neuropeptides (Schwartz et al. 2000, Ramos et al. 2005). in the ARC (Minokoshi et al. 2004, Lopez et al. 2008). Smokers are reported to have reduced level of NPY, For example, the AgRP increases the activity of AMPK in whereas smoking cessation is linked with increased the hypothalamus, whereas AMPK activity is inhibited levels of NPY (Hussain et al. 2012). In animal studies, by leptin in the ARC and PVN, as well as by insulin mice chronically exposed to low-dose nicotine showed in multiple hypothalamic areas (Minokoshi et al. decreased NPY levels in the PVN (Chen et al. 2007) and 2004). Likewise, changes in the activity of AMPK in ARC (Frankish et al. 1995), as well as reduced NPY receptor the hypothalamus regulate the expression of these density in the hypothalamus (Kane et al. 2001), together neuropeptides (Minokoshi et al. 2004). with a nicotine-dependent increase in the activity of Studies performed in rats showed that nicotine POMC neurons (Huang et al. 2011). This suggests that downregulates AMPK activity in the hypothalamus, chronic administration of nicotine, by decreasing the and this effect mediates a decrease in food intake and level of NPY and upregulating the activity of POMC BAT activation, as well as an increase in lipid oxidation. neurons, may negatively affect food intake and energy Conversely, genetic overactivation of AMPK in VMH can balance. However, further research is needed in this area reverse nicotine-induced weight loss and normalize the to establish a causal relationship between weight gain mRNA levels of NPY, AgRP and POMC in ARC (Martinez and increased NPY levels in the hypothalamus following de Morentin et al. 2012). Taken together, these data nicotine cessation. suggest that nicotine, by acting at peripheral and central Two other neuropeptides involved in regulation of levels, modulates food intake and energy homeostasis and feeding behavior are melanin-concentrating hormone controls the expression of several neuropeptides in the fat (MCH) (Van Bockstaele et al. 2000) and hypocretin (also cells and hypothalamus to exert its regulatory action on known as orexin), both of which are produced in the food intake and energy expenditure.

lateral hypothalamus (Skofitsch et al. 1985). It has been (CPP) in rats (Cohen et al. 2004, Le Foll & Goldberg 2004), showed that the increase in either MCH or hypocretin indicating that endocannabinoid signaling is involved in stimulates food intake (Qu et al. 1996, de Lecea et al. nicotine reinforcement and reward. Endocannabinoids 1998). Interestingly, self-administration of nicotine in stimulate appetite through different brain regions, such rats has been associated with increased expression of as limbic system (responsible for hedonic evaluation of hypocretin receptor mRNA in ARC (LeSage et al. 2010). food), hypothalamus, hindbrain, but also peripherally, at The modulation that nicotine exerts on the expression of the level of adipose tissue and intestinal system (Fride et al. peptides in ARC is more significant by considering that 2005). Blocking CB1 receptor in mice reduces appetite and ARC also integrates the signal coming from peripheral lipogenesis in WAT (Cota et al. 2003). Chronic nicotine organs and the rest of the CNS in order to execute the administration was shown to reduce body weight in wild- command for feeding behavior. For example, when the type, but not in CB1−/− mice (Bura et al. 2010), suggesting level of sugar rises in the blood circulation, it leads to that nicotine-mediated weight loss might be by the the release of insulin from the pancreas, which not only endocannabinoid system. More specific genetic approach increases the uptake of sugar by the muscle and liver, but in mice demonstrated that targeted deletion of CB1 also inhibits NPY/AgRP-containing neurons and stimulates receptor in cortical glutamatergic neurons reduces food POMC/CART-containing neurons in the ARC, leading to intake (Bellocchio et al. 2010), suggesting that the decrease satiety. Similar effect is induced by leptin released from level of endocannabinoids in cortex observed with chronic the fat cells (Schwartz et al. 2000). Thus, nicotine regulates nicotine administration (Gonzalez et al. 2002) might energy homeostasis by influencing the secretion of insulin represent one of the mechanisms of nicotine-induced and leptin by regulating the expression of neuropeptides weight loss. in specific hypothalamic nuclei. Interplay between rewarding effect of food and Hypothalamic neurons also produce endocan- nicotine was also found in human studies where neuronal nabinoids, which play a critical role in maintaining a circuits activated by food rich in sugar and fat overlapped precise equilibrium between caloric intake and energy with those observed by smoking (Volkow et al. 2008).

Endocrinology expenditure, storage and transport, factors that Moreover, absence of smoking increases the reward of keep body weight stable over time (Valassi et al. 2008, threshold for food (Kenny & Markou 2006), suggesting Cristino et al. 2014). that greater amount of highly rewarding food is sought in The endocannabinoid system is composed of the order to satisfy the rewarding effect previously achieved Journal cannabinoid receptors (CB1 and CB2), their endogenous with nicotine (Spring et al. 2003). An intriguing proposal ligands, like N-arachidonoylethanolamine (AEA) and is that nicotine may hijack the reward circuit and devalue 2-arachidonoylglycerol (2-AG), the enzymes that produce the motivational valence of food, thereby leading to and inactivate endocannabinoids, and endocannabinoid decrease in food intake. However, further studies are transporters (Piomelli 2003, Gardner 2005). Cannabinoid needed to test this possibility. CB1 receptors are present in the ventral tegmental area Additionally, nicotine has been shown to activate the (VTA) and the nucleus accumbens (NAc) and in several hypothalamic–pituitary–adrenal (HPA) axis, as shown by areas projecting to these two structures, including the increases in the level of the stress hormone, i.e., cortisol in prefrontal cortex, central amygdala and hippocampus, human/corticosterone in rodents (Rohleder & Kirschbaum and they appear to play an important role in brain 2006). This process involves the release of CRH/CRF, reinforcement/reward processes (Maldonado et al. 2006, which is known to exert anorexigenic effect (Glowa & Solinas et al. 2008). Gold 1991, Uehara et al. 1998). Thus, it is possible that Recent studies have implicated endocannabinoids in nicotine, by activating the HPA axis and causing the the pharmacological and behavioral effects of nicotine. release of CRH exerts its inhibitory effects on food intake. For example, chronic nicotine injections increased However, further studies are needed in this area to test endocannabinoids levels in the limbic forebrain and this possibility and related research questions. brainstem, but decreased levels in the hippocampus, striatum and cerebral cortex (Gonzalez et al. 2002), the Effects of nicotine on peripheral regulatory mechanisms same areas involved in the reinforcing/rewarding effects of energy homeostasis of addictive drugs (Koob et al. 1998). Moreover, a CB1 receptor antagonist, rimonabant, decreased nicotine The metabolic status of the body is also dependent on self-administration and conditioned place preference endocrine signals produced by the gastrointestinal

system. Enteroendocrine cells of the gastrointestinal desensitization of nAChR as a result of chronic nicotine tract produce and release hormones to promote appetite use, thereby giving a possible explanation for reduced (such as ghrelin) or satiety (e.g., cholecystokinin (CCK), food intake in smokers. glucagon-like peptide-1 (GLP-1), peptide tyrosine tyrosine Leptin and insulin have overlapping intracellular (PYY) and serotonin). Administration of serotonin in signaling mechanisms and exert anorexigenic actions in the the PVN, VMH and DMN of rats results in inhibition of hypothalamus. Leptin, which is secreted predominantly food intake (Sleight et al. 1995, Leibowitz & Alexander from WAT, provides feedback information on the amount 1998). Ghrelin is an important hormone produced by of fat stores to the ARC, PVN, LHA and the DMN of the the enteroendocrine cells of the gastric fundus and is hypothalamus, by acting on the long form of the leptin released before a meal and its amount is reduced after receptor (OB-Rb) (Meister 2000, Woods & D’Alessio a meal. Ghrelin regulates appetite by stimulating the 2008). Leptin binding to OB-Rb in hypothalamus initiates AgRP- and NPY- containing neurons in the ARC as well tyrosine phosphorylation by janus tyrosine kinase 2 as the NST, which in turn increases food intake (Gil- (JAK2). Phosphorylated JAK2 recruits and phosphorylates Campos et al. 2006). signal transducer and activator of transcription 3 (STAT3). Nicotine has been shown to alter mRNA expression The activated STAT3 dimerizes and translocate to the and plasma levels of several gastrointestinal hormones nucleus, stimulating gene transcription (Vaisse et al. (Chowdhury et al. 1990, Gomez et al. 1996). For example, 1996). Studies aimed to investigate the consequences of smoking in human subjects acutely elevated the plasma nicotine exposure during lactation, showed that offspring level of ghrelin, an orexigenic hormone (Bouros et al. of lactating rats infused with nicotine (6 mg/kg per day), a 2006). In another study, total plasma ghrelin levels were dose that produces serum nicotine levels similar to those measured before and after smoking two cigarettes in non- observed in typical smokers, results in lower expression smokers and habitual smokers who underwent overnight of OB-R, JAK2 and phosphorylated STAT3 with higher fasting and also remained abstinent from smoking. It suppressor of cytoskeleton signaling 3 (SOCS3) expression was found that the total plasma ghrelin level declined in the hypothalamus, indicating that nicotine induces

Endocrinology progressively in non-smokers, but not in smokers leptin resistance via the same intracellular pathways as of (Kokkinos et al. 2007). Given that the fasting plasma leptin (de Oliveira et al. 2010). Chronic administration ghrelin level was similar between habitual smokers and of nicotine in rats was shown to increase expression of non-smokers, the authors concluded that the decline in Ob-Rb and leptin-binding sites within the hypothalamus Journal plasma ghrelin induced by acute nicotine may be blunted of rats, while plasma leptin level remained reduced in in smokers due to desensitization as a result of habitual WAT and BAT (Li & Kane 2003). In a different study, nicotine use (Kokkinos et al. 2007). Furthermore, the chronic nicotine use in the form of nicotine gum or plasma ghrelin levels decrease following two months cigarette smoking caused an increase in circulating leptin of successful abstinence from nicotine (Lee et al. 2006), level compared to control subjects, which was linked and that systemic elevation of plasma ghrelin occurred to the low body weight in nicotine users than control in acute but not in chronic smokers (Bouros et al. 2006), (Eliasson & Smith 1999). indicating that the desensitization induced by chronic Insulin is also a critical regulator of energy homeostasis. nicotine exposure is overcome after nicotine cessation. As with leptin, insulin receptors are widely distributed in Ghrelin was shown to increase food intake and this the brain, with higher concentrations in the ARC. In vivo response was reduced by systemic administration of and in vitro data have demonstrated that both leptin mecamylamine, a centrally acting nAChR antagonist, and insulin exert their metabolic functions by activating despite the animals were fasted overnight. In contrast, the similar signaling pathways, including those that promote peripherally acting nAChR antagonist, hexamethonium, glucose uptake and glycogen storage through activation failed to alter food intake in these animals, suggesting that of JAK2, that in turn phosphorylates insulin receptor the ability of ghrelin to increase food intake is mediated substrate 2 (IRS2) to activate phosphoinositide 3-kinase at least in part via the central nAChRs (Dickson et al. (PI3K), thereby increasing SOCS3 expression (Tanaka et al. 2010). Additionally, fasting-induced food intake was 2009, Burgos-Ramos et al. 2011). Interestingly, there reduced by mecamylamine in this study, suggesting that are reports that chronic nicotine administration rewarding properties of food is mediated via the nAChRs, (3 mg/kg/day/subcutaneously) for 6 weeks enhances insulin and this response might be reduced in smokers due to sensitivity in normal rats, by activating hypothalamic

α7-nAChR-STAT3 signaling pathway (Xu et al. 2012), subjects (Axelsson et al. 2001, Morgan et al. 2004). Long- the same pathway used by leptin to control appetite and term nicotine gum or nicotine patch replacement in body weight, as well as lipid and energy metabolism. previous smokers is associated with insulin resistance Long-term oral nicotine administration reduces insulin (Assali et al. 1999). These discrepancies between clinical resistance in obese rats (Liu et al. 2003). Furthermore, oral and animal studies may be the result of difference in the administration of α7-nAChR-selective agonist in leptin- duration and route of nicotine administration as well as resistant db/db obese mouse for 7 weeks prevented further the nutritional status of the subjects. weight gain, reduced food intake and improved plasma Leptin exerts its regulatory actions on food intake glucose level (Marrero et al. 2010). Likewise, nicotine via homeostatic and reward mechanisms. During fasting, infusion via osmotic minipumps showed differential the levels of circulating leptin decreases, resulting in the effects on leptin levels, a decrease in the levels of leptin activation of NPY- and AgRP-containing neurons and was observed after 4 days of nicotine administration, the secretion of the orexigenic peptides (NPY and AgRP) whereas an increase was observed when nicotine infusion (Enriori et al. 2006, Ahima 2008), which induces feelings was continued for 14 days compared with their respective of hunger (Schwartz et al. 2000). In a fed state, an increase controls (Arai et al. 2001). Interestingly, the increase in in leptin level stimulates the secretion of anorexigenic leptin levels was also dependent on the type of adipose peptides, such as α-MSH and CART from ARC that tissue, being higher in omentum, retroperitoneal and projects to the LHA and PFA, resulting in satiety sensation epididymal WAT (Arai et al. 2001), suggesting that long- (Stanley et al. 1993, Ahima 2008). term nicotine administration induces tissue-selective Similarly to leptin, insulin acts in the ARC during leptin secretion. feeding phase and its action is to inhibit NPY/AgRP- and With regard to insulin, it has been demonstrated stimulate POMC-containing neurons to prevent further that rats fed with high-fat diet and treated with daily food intake and contribute to the feeling of satiety subcutaneous nicotine injections for 8 days, show (Plum et al. 2006). Moreover, it has been shown that a significant reduction in body weight, food intake, intracerebroventricular administration of PI3K inhibitors

Endocrinology insulin levels, improved serum lipid profile and in rodents, blocks the ability of leptin and insulin, of reduced hepatic steatosis (Seoane-Collazo et al. 2014), but no other anorexigenic substances, to reduce food indicating an improvement in insulin sensitivity. intake, indicating that both hormones utilize the same However, studies with chronic administration of intracellular pathways and confirming the importance Journal nicotine using minipumps for 4 weeks in mice showed of their interaction in the maintenance of metabolic AMPKα-dependent nicotine-induced insulin resistance homeostasis (Niswender et al. 2003). (Wu et al. 2015). Clinical studies aimed to investigate As with leptin and insulin, nicotine also regulates the effects of chronic nicotine on leptin levels showed metabolic homeostasis at both peripheral and central that leptin secretion was negatively correlated with levels, although the exact mechanisms have not yet chronic nicotine consumption and that leptin plasma been elucidated (Tweed et al. 2012). Clinical studies concentration increases 8 weeks after cessation of in populations with metabolic syndrome show that, smoking, in proportion to the gain in body weight independent of the weight, there are discrepancies in (Eliasson & Smith 1999). Overall, these studies suggest the distribution of adipose tissue. Some studies have that chronic administration of nicotine may have reported that chronic smoking actually increased positive outcome on metabolism in obesity and that the fat accumulation, which was accompanied with increase of leptin observed after chronic administration central obesity and insulin resistance (Barrett-Connor of nicotine, may be the result of the increase of plasma & Khaw 1989). Similar studies showed that smokers have insulin concentration as a consequence of the insulin higher level of plasma triglycerides and lower level of high resistance induced by long-term tobacco smoking. density lipoprotein cholesterol (HDL) (Facchini et al. The report of the pathways by which nicotine acts 1992). Long-term smokers had higher waist-to-hip ratio to enhance insulin and leptin sensitivity gives a better compared to non-smokers, even though they were not perspective on the real effects of nicotine on energy heavier than non-smokers (Kim et al. 2012). Moreover, homeostasis, since results from clinical and animal the waist-to-hip ratio correlated with increase in the studies are inconsistent. Some clinical studies reported number of cigarettes consumed (Clair et al. 2011). A that nicotine infusion acutely impairs insulin sensitivity positive correlation was found between body mass in type 2 diabetic patients and smokers but not in healthy index (BMI) and increase in cigarette smoking in obese

and morbidly obese subjects, suggesting that Control of feeding by nicotinic cholinergic α3β4 subunit- smoking might be more rewarding in this population containing receptors (Chiolero et al. 2008). Besides, it has been reported that Nicotine has been shown to reduce food intake and weight diabetic patients have lower rate of smoking cessation gain by modulating the function of melanocortin system than non-diabetic smokers (Solberg et al. 2004, Gill et al. through α3β4*-containing nAChRs (Mineur et al. 2011). In 2005). In conclusion, the effects of smoking on specific particular, nicotine activates α3β4* nAChRs expressed on metabolic outcomes is somewhat complex, as smoking POMC neurons in the ARC nucleus of the hypothalamus seems to contribute to weight loss in obese populations, (Mineur et al. 2011) that project to the PVN. Binding of while contributing to the development of central obesity nicotine to α3β4* nAChRs leads to depolarization of POMC- and type-2 diabetes in lean smokers. Further research is containing neurons in the ARC, which in turn results in needed in this area to define the underlying mechanism the release of α-MSH (Cone 2005) and activation of MCRs of this dichotomy. located in PVN, thereby leading to reduced food intake (Mineur et al. 2011). Consistent with this notion, POMC knockout mice were shown to be resilient to the inhibitory Role of nicotinic receptors in regulation of effect of nicotine on food intake (Mineur et al. 2011). energy homeostasis

Nicotine exerts its effects on energy homeostasis via Control of feeding by nicotinic cholinergic β2 subunit- nAChRs (Benowitz 2010). The nAChRs are widely containing receptors expressed throughout the brain and particularly well positioned in the hypothalamus (Wada et al. 1989, Recent studies have indicated that activation of β2*- O’Hara et al. 1998), to alter the function of neurons containing nAChRs similar to α3β4* nAChRs regulate the containing neuropeptides that regulate appetite and function of melanocortin system to reduce food intake food intake, thereby modulating energy homeostasis and body weight gain in mice (Dezfuli et al. 2016). A and feeding behavior (Mineur et al. 2011). Nicotine has relatively selective ligand of β2*-containing nAChRs Endocrinology sazetidine-A (SAZ-A) significantly reduced body weight of also been shown to change the level of certain peptides in the periphery that may also play a functional role in and food intake in obese mice (Dezfuli et al. 2016). the ability of nicotine to alter food intake. The nAChRs Specifically, chronic desensitization ofβ 2 nAChRs with Journal are also found in brain areas involved in motivation and continuous infusion of SAZ-A via subcutaneous osmotic reward (Naude et al. 2016) and thus may be involved in pump resulted in reduction in body weight gain and food the actions of nicotine on hedonic aspect of food intake intake, and these changes were not observed in β2−/− and (Lutter & Nestler 2009). MCR4−/− mice (Dezfuli et al. 2016). These findings suggest The nAChRs are ligand-gated ion channels that β2 nAChRs might have an important role in regulation comprising five transmembrane subunits, which may be of food intake through melanocortin system. However, arranged in a αβ-combinations (α2–α6 and β2–β4; e.g., further studies are needed in this area to determine if the α3β4* containing nAChRs; the asterisk refers to one absence of β2 subunit-containing nAChRs would cause or more additional subunits that could be associated alterations in the function of α3β4* containing nAChRs with the receptor), homomeric nAChRs (α7–α9) and a or vice versa and if that these variations could regulate heteromer α-combination (α9 with α10) (McGehee et al. food intake and body weight. 1995, Jones et al. 1999, Dani & Bertrand 2007). An earlier in situ hybridization study showed that there are Control of feeding by nicotinic cholinergic α4β2 subunit- moderate-to-high levels of expression of α4, α7 and β2 containing receptors mRNA in the hypothalamus (Jo et al. 2002), suggesting that these nAChRs subunits might be predominately Expression analysis within the hypothalamus has involved in the regulation of appetite control by identified α4β2 subunits of nAChRs in LHA, ARC and nicotine. Depending on the dose and duration of PVN (Wada et al. 1989). Furthermore, α4β2 nAChRs are nicotine exposure, nAChRs can either be desensitized or found on axons and cell bodies of dopaminergic neurons upregulated, thereby leading to different metabolic and (Zoli et al. 2002), where it is involved in nicotine-induced behavioral effects by nicotine. dopamine release (Grady et al. 1992) and nicotine reward

(McGranahan, 2011 #1592). Activation of these receptors (Huang et al. 2011). On the other hand, levels of NPY were in the LHA appears to reduce food intake. Systemic, as shown to be lower in smokers and also to be increased well as local administration of α4β2 receptor antagonist, during nicotine cessation, suggesting that NPY has di-hydro-β-erythroidine (DHβE) in LHA of fasted rats important role in control of food intake and body weight led to increased food intake in comparison to saline- gain following smoking cessation (Hussain et al. 2012). In treated controls (García et al. 2015). It is considered similar fashion, α7 nAChR antagonist MLA reduced the that modulatory action of endogenous ACh is mediated excitation of NPY by nicotine (Huang et al. 2011). by α4β2 nAChRs, which was shown previously to Aside from modulating the activity of neurons in the affect the release of serotonin and dopamine in LHA hypothalamus, α7 nAChRs have also been implicated in (Meguid et al. 2000). This may be induced by a direct the release of neurotransmitters, such as -aminobutyric activation of α4β2 nAChRs in the LHA, as application of acid (GABA), glutamate, serotonin and dopamine. DHβE on hypothalamic slices inhibited nicotine-induced Nicotine administration can facilitate activation of GABA depolarization of POMC neurons (Huang et al. 2011). In activity (Jo et al. 2002) and application of the α7 nAChR- another study, selective agonist of α4β2 receptor ((R,E)-5- specific antagonist (α-bungarotoxin) diminished this (2-pyrrolidin-3-ylvinyl)-pyrimidine) reduced food intake effect (Zhang & Berg 2007), suggesting that the increase and body weight without affecting metabolic parameters in GABAergic neuronal activity in the hypothalamus may such as glucose and triglyceride levels (Marrero et al. 2010). mediate the anorexigenic effect of nicotine. Replacement of nicotine with chronic administration of The role of α7 nAChR in modulating the dopamine SAZ-A, a potent nAChR partial agonist (Xiao et al. 2006) release in connection to food intake is somewhat intricate. that causes desensitization of α4β2 nAChRs, was shown Taking into account that α7 nAChRs are widely expressed to reverse the upregulation of the receptor induced by in the VTA, nicotine-induced activation of these receptors chronic nicotine administration. Besides, this drug, contributes to the release of glutamate (Schilstrom et al. like nicotine, was able to reduce body weight in rats 1998, 2000), which ultimately leads to increases in (Hussmann et al. 2014). Therefore, it may be that weight- dopaminergic activity and release of dopamine in the

Endocrinology reducing effect of nicotine is mediated, at least in part, by NAc. In that regard, it is considered that α7 nAChRs of its action on POMC neurons via the α4β2 nAChRs. contribute to the increased rewarding aspects of food (Schilstrom et al. 1998). On the other hand, elevated release of dopamine from dopaminergic projections to the Journal Control of feeding by nicotinic cholinergic α7 subunit- LHA and VMH by nicotine is correlated with reduction in containing receptors food intake (Meguid et al. 2000). The α7 nAChRs are also found on serotonergic Despite the relevance of majority of nicotinic receptors neurons (Galindo-Charles et al. 2008) and their activation being involved in control of feeding behaviors (Jo et al. by nicotine leads to the release of serotonin (Summers 2002, Mineur et al. 2011), it is considered that the most & Giacobini 1995). Serotonin inhibits food intake prominent action of nicotine in control of feeding is (Waldbillig et al. 1981) and this is considered to be accomplished through the activation of 7 nAChRs. α regulated via the inhibitory action of serotonin on NPY Neurons containing 7 nAChRs are found in the ARC α neurons, where it reduces the release of NPY (Dryden et al. nucleus, VMH and DMN (Seguela et al. 1993). Apart 1996). Ultimately, nicotine-induced activation of nicotinic from the hypothalamus, 7 nAChRs are expressed on α receptors increases the release of serotonin from extrinsic dopaminergic neurons (Klink et al. 2001) and glutamatergic projections to the LHA, which contributes to appetite afferents projecting to the VTA (Jones & Wonnacott suppression (Jo et al. 2002). 2004). Stimulation of α7 nAChRs was shown to suppress food intake via its actions in the hypothalamus (Jo et al. 2002). The α7 nAChRs are expressed on both POMC and Nicotine and obesity-induce inflammation NPY expressing neurons in the ARC nucleus and nicotine and insulin resistance exerts its action on feeding behaviors by modulating the activity of these neurons. For example, an in vitro study Gene expression analysis studies in adipose tissue have showed that the effect of nicotine was reduced in isolated revealed an increased expression of inflammatory markers POMC neurons through the application of the α7 nAChR in obese animals (Weisberg et al. 2003). Conversely, after non-selective antagonist methyllycaconitine (MLA) weight loss in obese individuals, decreased expression

(Clement et al. 2004) and secretion (Arvidsson et al. 2004) In addition, studies have shown that higher of pro-inflammatory components have been reported. circulating IL-6 promotes a shift in peptide production The adipose tissue itself in obese individuals is thus a site from glucagon toward glucagon-like peptide 1 (GLP-1), of production of inflammatory markers (Wisse 2004). As thus promoting functional beta-cell compensation to in human and rodent models of obesity, a correlation maintain proper insulin secretion and glucose homeostasis was observed between the number of macrophages and (Ellingsgaard et al. 2008). Moreover, knockout of IL-6 in the total amount of body fat, it was suggested that in mice or neutralization of IL-6 in wild-type mice fed with obese subjects, the adipose tissue is actually in a pro- high-fat diet caused impairment of glucose homeostasis inflammatory state Weisberg ( et al. 2003, Wisse 2004). (Ellingsgaard et al. 2011), indicating that an adipose tissue- The increased accumulation of macrophages in endocrine-islet loop exists that could be regulated in WAT tissue may contribute to the enhanced systemic some extent by nicotine-induced IL-6 secretion, inducing concentrations of pro-inflammatory cytokines in metabolic adaptations that could result in weight loss in obesity. Not only tumor necrosis factor-alpha (TNF-α obese smokers. It does not explain, however, the presence but also interleukin-6 (IL-6) (Lehrke et al. 2004) are of insulin resistance observed in chronic smokers. It may known to interact directly with the insulin signaling be a consequence of the desensitization that chronic cascade (Kershaw & Flier 2004, Trayhurn & Wood 2004, nicotine exposure induces on α7 nAChRs, reducing Wisse 2004), leading to the development of insulin circulating IL-6, therefore reducing GLP-1 secretion. It is resistance usually linked to obesity. Chronic cigarette accepted now that apart from its central action, nicotine smoking has been associated with elevated circulating activation of α7 nAChRs expressed on certain cells of the levels of inflammatory cytokines, such as TNF-α and IL6 immune system may affect metabolic homeostasis. This is (Fernandez-Real et al. 2003, Ellingsgaard et al. 2008). a new field that is being explored nowadays. Aside from its central action, nicotine acting on α7 nAChRs expressed on immune cells may affect metabolic homeostasis. Recruitment of α7 nAChRs Effects of nicotine on hedonic aspects of

Endocrinology inhibits activation of pro-inflammatory nuclear factor-B feeding of (NF-B) signaling cascade in macrophages, that in turn reduces local inflammation Pavlov ( et al. 2003). The Cigarette smoking constitutes a significant public health anti-inflammatory action of nicotine, like that of the matter and is associated with increased risk of early Journal endogenous neurotransmitter acetylcholine (ACh), is due morbidity and mortality. This becomes an even greater to the binding to and activation of α7 nAChRs on resident subject of concern if consider that nicotine, the primary macrophages under the control of the ‘cholinergic anti- psychoactive substance in tobacco smoke, activates inflammatory pathway’ (CAP) Borovikova ( et al. 2000, mesolimbic dopaminergic signaling pathways, which Wang et al. 2003, Tracey 2007). The α7 nAChRs activation are important component of the reward system in the by ACh released from the efferent vagus nerve may be brain and is implicated in the development of addiction important in this regard (Borovikova et al. 2000). Clinical (Nestler 2005, Criscitelli & Avena 2016). Nicotine also studies showed that the expression of α7 nAChR was plays an important role in the modulation of food intake reduced in fat cells isolated from subcutaneous adipose and metabolism. As with nicotine, highly palatable foods tissue of obese human subjects (Cancello et al. 2012). are also capable of altering dopamine release within this Moreover, oral application of specificα 7 nAChR agonist system, giving place to addictive responses in susceptible in leptin-resistant db/db obese mice reduced food intake individuals (Zoli & Picciotto 2012). and weight gain in these mice (Marrero et al. 2010). α7 In support of this notion, there is a large body of nAChRs play a major role in the central and peripheral evidence showing that motivational aspects of certain regulation of food intake and energy homeostasis. foods and drugs of abuse share similar reward pathways. Furthermore, nicotine, acting on α7 nAChRs may inhibit For example, nicotine mediates its rewarding effect by the activation of pro-inflammatory cytokines, limiting directly stimulating dopaminergic transmission from VTA the inflammatory state of obese smokers, and helping to NAc and food produces similar responses within the in reducing body weight. Although complex, activation mesolimbic system (Nestler 2005). of α7 nAChRs is critical in suppression of appetite and Preclinical and clinical studies demonstrate that reduction of body weight gain. despite strong commitment of smokers to stop smoking,

the addictive properties of nicotine makes cessation Administration of mecamylamine suppressed sucrose from smoking too difficult (Goodman et al. 2008). For intake (Shariff et al. 2016), pavlovian incentive motivation example, out of 70% smokers who try to quit smoking, (Ostlund et al. 2014) and operant self-administration of only 7% were reported to achieve long-term abstinence sucrose at higher doses (Ford et al. 2009). from tobacco use (Goodman et al. 2008). Furthermore, Projections from the shell of NAc to the lateral among human population, nicotine mechanisms of hypothalamus and striatopallidal system, which addiction seem to be related with the concentration and are regulated by opioids, endocannabinoids and distribution of adipose tissue, as individuals with higher dopaminergic input, respond and mediate the sensory BMI smoke more cigarettes per day than non-smokers properties of palatable food as well as that of drugs of (Rupprecht et al. 2015). Moreover, results obtained from abuse, such as nicotine (Kenny 2011a,b). Consumption human studies showed that nicotine was less rewarding to of palatable food and drugs of abuse also induces obese non-deprived smokers, as measured by percentage changes in striatal reward circuits through the action of of total puffs taken from cigarettes with normal nicotine hormones and neuropeptides. Hypocretin and MCH are content (Blendy et al. 2005). On the other hand, obese two neuropeptides that not only regulate food intake, but participants were experiencing higher hedonic effect also mediate the rewarding properties of drugs of abuse with cigarettes that were containing lower content of by modulating the function of mesolimbic dopaminergic nicotine (Rupprecht et al. 2015), suggesting that obese neurons (Zheng et al. 2007, Chung et al. 2009). The MCH people might be more prone to smoking, while increased receptors are expressed in the NAc, activation of which smoking in obese population might be related to lower stimulates feeding behaviors (Georgescu et al. 2005). On rewarding effect of nicotine (Rupprecht et al. 2015). the other hand, inhibition of MCH receptors in the NAc Studies performed in rodents displayed similar results. diminished cocaine-induced CPP (Chung et al. 2009). Mice fed a high-fat diet failed to display preference to Likewise, alcohol CPP was decreased in MCH1-R knockout nicotine in CPP paradigm indicating that, consumption mice (Karlsson et al. 2016), suggesting that MCH signaling of palatable food can alter normal reward processing might also be involved in the rewarding effect of nicotine.

Endocrinology (Blendy et al. 2005, Kenny 2011), which may explain Blockade of hypocretin receptor in insula reduces nicotine of the difference in smoking habits between lean and obese self-administration in rats (Hollander et al. 2008). human population. Nicotine-induced CPP as well as nicotine withdrawal Regulation of food intake by dopamine takes place were attenuated in mice lacking the preproenkephalin gene Journal in the hypothalamus through the action of dopamine on compared to their wild-type controls (Berrendero et al. its receptors, D1 and D2 receptors (Ramos et al. 2005). In 2005), suggesting that opioids derived from proenkephalin the hypothalamus, release of dopamine is associated with are involved in the rewarding effect of nicotine as well as increased duration of food intake. Free-feeding rats treated nicotine dependence. The significance of POMC signaling with repeated systemic administration of D1 agonist (SKF on nicotine reward was shown in an earlier study, where 38393) exhibit decrease food intake, while D2 receptor mice lacking beta-endorphin displayed reduced nicotine- agonist (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) induced CPP (Trigo et al. 2009). Mice lacking beta- has opposite effects in the same animal population (Rusk endorphin had higher body weight compared to their & Cooper 1989). Outside the hypothalamus, activation wild-type controls (Rubinstein et al. 1996), suggesting of D1 expressing neurons in the NAc has been reported that beta-endorphin may also be involved in energy to stimulate feeding behavior (Zhu et al. 2016). Released homeostasis and in the ability of nicotine to reduce body ACh from the cholinergic interneurons in the NAc binds weight. Considering that mice lacking POMC exhibited to nAChRs and influences the release of dopamine and blunted response to nicotine-induced reduction of food thus reward processing (Mark et al. 2011). Both acute and intake (Mineur et al. 2011) and that beta-endorphin is chronic nicotine treatment modulates the hedonic aspects derived from POMC, further research is needed to assess of food intake by increasing the release of dopamine the role of beta-endorphin in the ability of nicotine to from the ventral and dorsal striatum, through activation reduce body weight and energy homeostasis. of nAChRs, such as α4* and α6* containing nAChRs Nicotine administration was shown to reduce NPY (Grady et al. 2007, De Biasi & Dani 2011). Furthermore, immunoreactivity in the shell of NAc, PVN and ARC chronic long-term sucrose intake increased α4β2* while (Kotagale et al. 2014). Co-administration of NPY Y1 decreases α6β2 nAChRs in the NAc (Shariff et al. 2016). receptor potentiated the inhibitory effect of agmatine

on nicotine-induced CPP, suggesting that NPY signaling be due to reduced nicotine reward in these rats compared negatively affects nicotine-mediated reward processing to controls. However, further studies are needed to (Kotagale et al. 2014). However, further research is needed determine whether the differences are as a result of to define the underlying mechanism of the regulatory species differences (mouse vs rat), treatment (high fat vs action of NPY on nicotine reward and whether this is a streptozotocin) and/or experimental procedure (CPP vs direct effect of NPY or a combination of agmatine and NPY. drug self-administration paradigm). In addition to neuropeptides, hormonal regulator of Nicotine has been shown to serve as a gateway drug to appetite such as ghrelin increases motivation for food and promote the use of other addictive drugs, such as alcohol drug intake by activating cholinergic and dopaminergic and cocaine (Huang et al. 2013). Nicotine also appears systems (Jerlhag et al. 2006, Skibicka et al. 2011). to affect the reward threshold for natural reinforcing Ghrelin activates dopaminergic neurons of the VTA via agents, suggesting common mechanism for the gateway cholinergic input, leading to dopamine overflow in the action of nicotine. However, the effect of nicotine on NAc, suggesting that ghrelin may regulate motivational these reinforcers is different depending on the duration aspect of feeding behavior (Jerlhag et al. 2006). of nicotine administration and whether animals are Leptin receptors are expressed on dopaminergic neurons exposed to sucrose or fat, and even the content of fat in (Figlewicz et al. 2003) and leptin inhibits appetite by regulating food is important in this regard. Acute nicotine enhances the function of the mesolimbic neurons (Fulton et al. 2006). rewarding effect of palatable food. For example, mice with More specifically, leptin attenuates activation of striatal acute exposure to nicotine were found to have higher reward system, as it was shown that leptin replacement brake-point for sucrose in the operant conditioning reduces self-reported liking of food in humans (Farooqi et al. paradigm (Brunzell et al. 2006). Similarly, using CPP 2007). Infusion of leptin directly into the VTA inhibits paradigm, Buffalari and coworkers showed that animals activation of dopamine neurons (Hommel et al. 2006) and conditioned with cocaine or sucrose and tested for place decreases brain reward function in rats (Bruijnzeel et al. preference after a single nicotine challenge exhibited 2011). Mice fed a high-fat diet had reduced expression of greater preference for the sucrose- as well as cocaine-

Endocrinology leptin receptor in the VTA, and also did not exhibit nicotine paired compartment, showing that nicotine increased of CPP (Blendy et al. 2005), suggesting that increased leptin the motivational valence of contextual cue associated level in obesity attenuates reward processing in the brain via with cocaine as well as sucrose (Buffalari et al. 2014). an action on the activity of dopaminergic neurons. Animals fed on high-fat diet and exposed to chronic Journal Insulin is another hormone that regulates energy nicotine tend to maintain or even increase their body homeostasis. Insulin receptors are found to be expressed weight in comparison to their regular low-fat diet-fed in the VTA and NAc, suggesting that insulin is involved in controls (Wellman et al. 1986, Mangubat et al. 2012). the regulation of food intake by an action on dopaminergic Another similar study showed that chronic peripheral neurons (Zahniser et al. 1984, Figlewicz et al. 2003). In administration of nicotine induces reduction of body particular, insulin administration in the VTA decreases weight and increases BAT thermogenesis in groups of rewarding effect of palatable food (Figlewicz et al. rats fed either high or low-fat diet, suggesting that the 2008) by increasing reuptake of dopamine through the reinforcing effect of nicotine disappears after chronic dopamine transporter (Mebel et al. 2012). In contrast, exposure, but may be restored after the cessation of inactivation of insulin receptor in dopaminergic neurons nicotine use (Parker & Doucet 1995). leads to hyperphagia and weight gain (Konner et al. 2011). Diabetic rats are shown to have reduced level of dopamine in midbrain and striatum (Murzi et al. 1996), Summary and conclusions and streptozotocin-induced hypoinsulinemic rats showed increased nicotine self-administration (O’Dell et al. 2014). The regulation of feeding and metabolism by nicotine Similarly, insulin-resistant rats fed a high-fat diet showed appears somewhat complex, mainly because it acts at enhanced nicotine preference in the CPP paradigm different levels, both centrally and peripherally, to regulate (Richardson et al. 2014). This disrupted dopamine- multiple hormones and neuropeptides and their receptors mediated reward transmission induced by impaired to modify energy expenditure and feeding behavior. insulin signaling, may explain higher preference for Adipose tissue has a crucial role in metabolic nicotine intake in obese smokers. It also suggests that homeostasis and is one of the targets of nicotine’s action. higher self-administration of nicotine in diabetic rats may On the one hand, nicotine increases energy expenditure

and thermogenesis by enhancing the expression of results of these studies are expected to provide useful basic the mitochondrial carrier proteins UCP1 mRNA in BAT science information that may lay the foundation for the (Chen et al. 2006, Zoli & Picciotto 2012). On the other development of novel pharmacotherapy to treat nicotine hand, nicotine stimulates the secretion of adiponectin as well as food addiction and obesity. and leptin (hormones with autocrine, paracrine and endocrine functions) from WAT, which lead to reduced

food intake and increased metabolism, both effects Declaration of interest observed in tobacco smokers. Interestingly, experimental The authors declare that there is no conflict of interest that could be studies in rodents suggest that adiponectin increases perceived as prejudicing the impartiality of this review. insulin sensitivity in peripheral tissues (Matsuzawa 2006), whereas human studies report that long-term exposure to nicotine induces changes in fat distribution associated Funding with insulin resistance (Wu et al. 2015). Further studies This work was supported by a Tobacco Related Disease Research Program (TRDRP 24RT-0023) to K L. A S and E P E were supported in part by a SBIR show that resident macrophages located in WAT express Phase II Grant HHSN275201500005C. OF was supported by the Department 7αnAChR, and that once activated by nicotine, they of Pharmaceutical Sciences, College of Pharmacy at Western University of inhibit the secretion of pro-inflammatory cytokines. Health Sciences (Pomona, CA). This could be the cause of the weight loss observed in obese smokers, who present a mild state of chronic inflammation. However, it has also been shown that References long-term exposure to nicotine desensitizes its receptor, Ahima RS 2008 Revisiting leptin’s role in obesity and weight loss. Journal increasing the secretion of cytokines, a situation that may of Clinical Investigation 118 2380–2383. (doi:10.1172/JCI36284) Albanes D, Jones DY, Micozzi MS & Mattson ME 1987 Associations lead to fat redistribution, insulin resistance and worsening between smoking and body weight in the US population: analysis of the metabolic state. of NHANES II. American Journal of Public Health 77 439–444. Nicotine exerts its modulatory effects by binding to (doi:10.2105/ajph.77.4.439) An Z, Wang H, Song P, Zhang M, Geng X & Zou MH 2007 Nicotine-

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Received in final form 18 June 2017 Accepted 17 July 2017